title: Molecular mechanism of immunoglobulin V-region diversification regulated by transcription and RNA metabolism in antigen-driven B cells.
abstract: The immune system produces specific antibodies (Ab) against any antigens (Ag) of exogenous and endogenous origins with a diverse repertoire of V-region specificities. The primary V-region repertoire is created by the rearrangement of immunoglobulin (Ig) V-region, D- and J-segments with the insertion of N- and P-sequences during early B cell differentiation. Recent studies revealed that secondary diversification of the IgV-region generated in the peripheral lymphoid organs plays a critical role in the generation of effective Ab production for protection from various pathogens. Naïve B cells that react with Ags initiate proliferation and differentiation in the follicular region and create the germinal centres (GCs), where activation-induced cytidine deaminase (AID)-dependent IgV-region somatic hypermutation (SHM) and class-switch recombination generate high-affinity and class-switched mature Ag-specific B cells. Our studies have discovered a 210-kDa nuclear protein, named GC-associated nuclear protein (GANP) that is up-regulated in GC B cells during the T cell-dependent (TD) immune responses. By studying mice with mutant forms of the ganp gene, we demonstrated that GANP is essential for the generation of high-affinity B cells against TD-Ag by affecting SHM at the IgV-regions. GANP is associated with AID in the cytoplasm and the GANP/AID complex is recruited to the nucleus, specifically, the chromatin, and targeted selectively to the IgV-region gene in B cells. GANP augments the access of AID towards IgV-regions in B cells. Here, we review the role of GANP in acquired immunity through the detailed analysis of the molecular mechanism generating SHM specifically at IgV-regions in B cells.
authors.affiliation: Department of Immunology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. nobusaka@kumamoto-u.ac.jp
authors.forename: N
authors.initials: N
authors.lastname: Sakaguchi
authors.forename: K
authors.initials: K
authors.lastname: Maeda
authors.forename: K
authors.initials: K
authors.lastname: Kuwahara
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics / Q000276:immunology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D003564:Cytidine Deaminase / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D012313:RNA / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics* / Q000276:immunology; D014158:Transcription, Genetic; D015854:Up-Regulation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C481510:GANP protein, mouse; D007135:Immunoglobulin Variable Region; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012313:RNA; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase